Impact of Tweeting Summaries by the Japanese Circulation Society Official Account on Article Viewership　- Pilot Trial.

BACKGROUND: The impact of promotional tweets from the official journal account (forCirculation JournalandCirculation Reports) on article viewership has not been thoroughly evaluated.Methods and Results:We retrospectively collected journal viewership data forCirculation JournalandCirculation Reportsfrom March 2021 to August 2021. We compared viewership between articles with (n=15) and without (n=250) tweets. After 1 : 4 propensity score matching (15 tweeted articles and 60 non-tweeted matched controls), journal viewership metrics within 7 days of the tweeting date (and the hypothetical tweeting date), was larger in tweeted articles than non-tweeted articles (median [interquartile range] Abstract page views 89 [60-104] vs. 18 [8-41]). CONCLUSIONS: This pilot study suggests a positive relationship between journal-posted promotional tweets and article viewership.

Recommendations for Maintaining the Cardiovascular Care System Under the Conditions of the COVID-19 Pandemic　- 1st Edition, April 2020.

BACKGROUND: The Japanese Circulation Society proposes recommendations for all healthcare professionals involved in cardiovascular medicine to protect them from infection and ensure that seriously ill patients requiring urgent care receive proper treatment.Methods and Results:Patients are divided into "Positive or suspected coronavirus disease 2019 (COVID-19)" and "All others". Furthermore, tests and treatments are divided into emergency or standby. For each category, we propose recommendations. CONCLUSIONS: To maintain the cardiovascular care system, The Japanese Circulation Society recommends completely preventing nosocomial COVID-19 infections, ensuring adequate PPE necessary for healthcare personnel, and learning and implementing standard precautions.

Coronavirus Disease 2019 (COVID-19) Information for Cardiologists　- Systematic Literature Review and Additional Analysis.

BACKGROUND: Despite the rapidly increasing attention being given to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, more commonly known as coronavirus disease 2019 (COVID-19), the relationship between cardiovascular disease and COVID-19 has not been fully described.Methods and Results:A systematic review was undertaken to summarize the important aspects of COVID-19 for cardiologists. Protection both for patients and healthcare providers, indication for treatments, collaboration with other departments and hospitals, and regular update of information are essentials to front COVID-19 patients. CONCLUSIONS: Because the chief manifestations of COVID-19 infection are respiratory and acute respiratory distress syndrome, cardiologists do not see infected patients directly. Cardiologists need to be better prepared regarding standard disinfection procedures, and be aware of the indications for extracorporeal membrane oxygenation and its use in the critical care setting.

Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction.

RATIONALE: Doxorubicin is an effective chemotherapeutic agent for cancer, but its use is often limited by cardiotoxicity. Doxorubicin causes endoplasmic reticulum (ER) dilation in cardiomyocytes, and we have demonstrated that ER stress plays important roles in the pathophysiology of heart failure. OBJECTIVE: We evaluated the role of ER stress in doxorubicin-induced cardiotoxicity and examined whether the chemical ER chaperone could prevent doxorubicin-induced cardiac dysfunction. METHODS AND RESULTS: We confirmed that doxorubicin caused ER dilation in mouse hearts, indicating that doxorubicin may affect ER function. Doxorubicin activated an ER transmembrane stress sensor, activating transcription factor 6, in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of activating transcription factor 6, including X-box binding protein 1. The decreased levels of X-box binding protein 1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein 78 which plays a major role in adaptive responses to ER stress. In addition, doxorubicin activated caspase-12, an ER membrane-resident apoptotic molecule, which can lead to cardiomyocyte apoptosis and cardiac dysfunction. Cardiac-specific overexpression of glucose-regulated protein 78 by adeno-associated virus 9 or the administration of the chemical ER chaperone 4-phenylbutyrate attenuated caspase-12 cleavage, and alleviated cardiac apoptosis and dysfunction induced by doxorubicin. CONCLUSIONS: Doxorubicin activated the ER stress-initiated apoptotic response without inducing the ER chaperone glucose-regulated protein 78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of glucose-regulated protein 78 or the administration of the chemical ER chaperone alleviated the cardiac dysfunction induced by doxorubicin and may facilitate the safe use of doxorubicin for cancer treatment.

Anti-HB-EGF Antibody-Mediated Delivery of siRNA to Atherosclerotic Lesions in Mice.

For atherosclerotic cardiovascular diseases (ACD), gene therapy may be a potential therapeutic strategy; however, lack of effective and safe methods for gene delivery to atherosclerotic plaques have limited its potential therapeutic applications. To overcome this limitation, we developed a novel antibody-based gene delivery system (anti-HB-EGF/NA vector) by chemically crosslinking antibodies against human heparin-binding epidermal growth factor-like growth factor (HB-EGF). It has been shown to be excessively expressed in human atherosclerotic plaques and NeutrAvidin (NA) for conjugating biotinylated siRNA. Immunofluorescence staining and quantitative flow cytometry analysis using human HB-EGF-expressing cells showed both antibody-mediated selective cellular targeting and efficient intracellular delivery of conjugated biotin-fluorescence. Moreover, we demonstrated antibody-mediated significant and selective gene knockdown via conjugation with anti-HB-EGF/NA vector and biotinylated siRNA (anti-HB-EGF/NA/b-siRNA) in vitro. Furthermore, using high fat-fed human HB-EGF knock-in and apolipoprotein E-knockout (Hbegf hz/hz; Apoe-/-) mice, we demonstrated that the anti-HB-EGF/NA vector, conjugating biotin-fluorescence, increasingly accumulated within the atherosclerotic plaques of the ascending aorta in which human HB-EGF expression levels were highly elevated. Moreover, in response to a single intravenous injection of anti-HB-EGF/NA/b-siRNA in a dose-dependent manner, qPCR analysis of laser-dissected atherosclerotic plaques of the ascending aorta showed significant knockdown of the reporter gene expression. These results suggest that the anti-HB-EGF antibody-mediated siRNA delivery could be a promising delivery system for gene therapy of ACD.

Development of a novel one-step production system for injectable liposomes under GMP.

There are few methods available for injectable liposome production under good manufacturing practices (GMP). Injectable liposome production processes under GMP generally consist of liposome formation, size homogenization, organic solvent removal, liposome concentration control and sterilization. However, these complicated and separate processes make it difficult to maintain scalability, reproducibility and sterility. To overcome these limitations, we developed a novel one-step in-line closed liposome production system that integrated all production processes by combining the in-line thermal mixing device with modified counterflow dialysis. To validate the system, we produced liposomal cyclosporine A (Lipo-CsA) and lyophilized the liposomes. The three independent pilot batches were highly reproducible and passed the quality specifications for injectable drugs, demonstrating that this system could be used under GMP. The accelerated stability test suggested that the liposomes would be stable in long-term storage. This one-step system facilitates a fully automated and unattended production of injectable liposomes under GMP.

Novel Synthesized Radical-Containing Nanoparticles Limit Infarct Size Following Ischemia and Reperfusion in Canine Hearts.

PURPOSE: Although nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) scavenge free radicals, their short half-life and considerable side effects such as systemic hypotension and bradycardia have limited their clinical application. Since a radical-containing nanoparticle (RNP) delivers nitroxyl radicals with a prolonged half-life specific to ischemic hearts, we investigated whether RNPs reduce infarct size without the occurrence of substantial side effects and whether nitric oxide (NO) contributes to the cardioprotective effects of RNPs. METHODS: The left anterior descending coronary arteries of dogs were occluded for 90 min, followed by reperfusion for 6 h. Either RNPs, micelles (not containing TEMPO) (control), or 4-hydroxy-TEMPO (TEMPOL) was injected into a systemic vein for 5 min before reperfusion. We evaluated the infarct size, myocardial apoptosis, plasma NO levels in coronary venous blood, and the RNP spectra using an electron paramagnetic resonance assay. RESULTS: RNPs reduced infarct size compared with the control group and TEMPOL group (19.5 ± 3.3 vs. 42.2 ± 3.7 vs. 30.2 ± 3.4%). RNPs also reduced myocardial apoptosis compared with the control and TEMPOL group. Coronary venous NO levels increased in the RNP group. CONCLUSIONS: In conclusion, the administration of 2,2,6,6-tetramethylpiperidine-1-oxyl as a RNP exerted cardioprotective effects against ischemia and reperfusion injury in canine hearts without exerting unfavorable hemodynamic effects. RNPs may represent a promising new therapy for patients with acute myocardial infarction.

Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice.

Incretin hormones, including glucagon-like peptide-1 (GLP-1), a target for diabetes mellitus (DM) treatment, are associated with cardioprotection. As dipeptidyl-peptidase IV (DPP-IV) inhibition increases plasma GLP-1 levels in vivo, we investigated the cardioprotective effects of the DPP-IV inhibitor vildagliptin in a murine heart failure (HF) model. We induced transverse aortic constriction (TAC) in C57BL/6J mice, simulating pressure-overloaded cardiac hypertrophy and HF. TAC or sham-operated mice were treated with or without vildagliptin. An intraperitoneal glucose tolerance test revealed that blood glucose levels were higher in the TAC than in sham-operated mice, and these levels improved with vildagliptin administration in both groups. Vildagliptin increased plasma GLP-1 levels in the TAC mice and ameliorated TAC-induced left ventricular enlargement and dysfunction. Vildagliptin palliated both myocardial apoptosis and fibrosis in TAC mice, demonstrated by histological, gene and protein expression analyses, and improved survival rate on day 28 (TAC with vildagliptin, 67.5%; TAC without vildagliptin, 41.5%; P < 0.05). Vildagliptin improved cardiac dysfunction and overall survival in the TAC mice, both by improving impaired glucose tolerance and by increasing GLP-1 levels. DPP-IV inhibitors represent a candidate treatment for HF patients with or without DM.

Liposomal amiodarone augments anti-arrhythmic effects and reduces hemodynamic adverse effects in an ischemia/reperfusion rat model.

PURPOSE: Although amiodarone is recognized as the most effective anti-arrhythmic drug available, it has negative hemodynamic effects. Nano-sized liposomes can accumulate in and selectively deliver drugs to ischemic/reperfused (I/R) myocardium, which may augment drug effects and reduce side effects. We investigated the effects of liposomal amiodarone on lethal arrhythmias and hemodynamic parameters in an ischemia/reperfusion rat model. METHODS AND RESULTS: We prepared liposomal amiodarone (mean diameter: 113 ± 8 nm) by a thin-film method. The left coronary artery of experimental rats was occluded for 5 min followed by reperfusion. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads accumulated in the I/R myocardium. Amiodarone was measurable in samples from the I/R myocardium when liposomal amiodarone, but not amiodarone, was administered. Although the intravenous administration of amiodarone (3 mg/kg) or liposomal amiodarone (3 mg/kg) reduced heart rate and systolic blood pressure compared with saline, the decrease in heart rate or systolic blood pressure caused by liposomal amiodarone was smaller compared with a corresponding dose of free amiodarone. The intravenous administration of liposomal amiodarone (3 mg/kg), but not free amiodarone (3 mg/kg), 5 min before ischemia showed a significantly reduced duration of lethal arrhythmias (18 ± 9 s) and mortality (0 %) during the reperfusion period compared with saline (195 ± 42 s, 71 %, respectively). CONCLUSIONS: Targeting the delivery of liposomal amiodarone to ischemic/reperfused myocardium reduces the mortality due to lethal arrhythmia and the negative hemodynamic changes caused by amiodarone. Nano-size liposomes may be a promising drug delivery system for targeting I/R myocardium with cardioprotective agents.

Lamr1 functional retroposon causes right ventricular dysplasia in mice.

Arrhythmogenic right ventricular dysplasia (ARVD) is a hereditary cardiomyopathy that causes sudden death in the young. We found a line of mice with inherited right ventricular dysplasia (RVD) caused by a mutation of the gene laminin receptor 1 (Lamr1). This locus contained an intron-processed retroposon that was transcribed in the mice with RVD. Introduction of a mutated Lamr1 gene into normal mice by breeding or by direct injection caused susceptibility to RVD, which was similar to that seen in the RVD mice. An in vitro study of cardiomyocytes expressing the product of mutated Lamr1 showed early cell death accompanied by alteration of the chromatin architecture. We found that heterochromatin protein 1 (HP1) bound specifically to mutant LAMR1. HP1 is a dynamic regulator of heterochromatin sites, suggesting that mutant LAMR1 impairs a crucial process of transcriptional regulation. Indeed, mutant LAMR1 caused specific changes to gene expression in cardiomyocytes, as detected by gene chip analysis. Thus, we concluded that products of the Lamr1 retroposon interact with HP1 to cause degeneration of cardiomyocytes. This mechanism may also contribute to the etiology of human ARVD.

Understanding International Differences in Academic Author Order in General Medicine Publications.

Objectives: With increasing multinational research in general medicine, the lack of a standardized policy regarding the order of author bylines can create conflict and misunderstanding due to different practices worldwide. Methods: We examined publicly available data from websites such as Journal Citation Reports and Web of Science, focusing on original articles published in the "Medicine, General, & Internal" category in 2020. Of 169 journals in the "Medicine, General, & Internal" category, we selected the ten countries with the highest number of publications and then examined the position of the corresponding author in the author byline as an indicator of the author in charge since corresponding authors are considered to have contributed the most. Results: The top ten countries with the highest publications are the USA, China, Germany, England, Japan, France, Italy, Canada, India, and Australia. The results demonstrated that the percentage of the second author being the corresponding author was the highest in Japan compared to other countries. This percentage was 25 times higher in Japan than in the USA. Conclusions: Understanding international differences regarding author order would facilitate smoother collaboration.

A cross-sectional survey on principal investigators' clinical research knowledge in Japan.

Principal investigators (PIs) play a key role in clinical research, and must thus understand the role of clinical research support staff to conduct successful and appropriate clinical research. This study evaluates clinical research capabilities by examining the clinical research knowledge of PIs and clinical research support staff. The participants of this cross-sectional study were academic researchers and clinical research support staff from Japanese universities and research institutions. The participants comprised of 54 respondents, among whom 36 were PIs (physicians) and 18 were clinical research support staff. A self-administered electronic survey was created and evaluated by experts, with 50 knowledge items. Mann-Whitney U tests were used to determine the significance of the differences in knowledge between clinical research support staff and PIs. We compared the correct answer rate of clinical research support staff and PIs for each knowledge category and observed that the clinical research support staff scored significantly higher than the PIs in all aspects of clinical research knowledge sections, including total score. Our findings showed that PIs did not have the same amount of clinical research knowledge as the clinical research support staff. Clinical research knowledge is essential for investigators, especially PIs, to protect patients and promote medical breakthroughs. Thus, more accessible clinical research education and mandatory knowledge testing will allow PIs to lead successful clinical research and further the level of medical research in Japan.

Difficulties in ensuring review quality performed by committees under the Act on the Safety of Regenerative Medicine in Japan.

We outlined five studies regarding the quality of the review by committees based on the Act on the Safety of Regenerative Medicine. The findings raise serious concerns about the independence, integrity, and quality of reviews of therapeutic plans by these committees with inappropriately close relationships to medical institutions and companies.

Impact of Tweet Content on the Number of Retweets　- "Tweet the Meeting 2022".

Background: Previous research has investigated the effectiveness of the "Tweet the Meeting" campaign, but the relationship between tweet content and the number of retweets has not been fully evaluated. Methods and Results: We analyzed the number of tweets and retweets during the Japanese Circulation Society's 2022 annual meeting. The ambassador group had significantly more session- and symposium-related tweets than the non-ambassador group (P<0.001), associated with the nubmer of retweets. Symposium-related tweets with figures generated more retweets than those without figures (mean [±SD] 3.47±3.31 vs. 2.48±1.94 retweets per tweet, respectively; P=0.001). Conclusions: The study revealed that official meeting-designated Twitter ambassadors disseminate more educational content than non-ambassadors, and generated more retweets.

Smoking promotes subclinical atherosclerosis in apparently healthy men: 2-year ultrasonographic follow-up.

BACKGROUND: Smoking is a major risk factor for cardiovascular disease. Also, inflammatory activation and metabolic disorder are the mediators of smoking-induced atherosclerotic progression. The aim of the present study was to investigate whether current smoking and smoking cessation alter inflammatory or metabolic status and affect subclinical atherosclerosis in apparently healthy men. METHODS AND RESULTS: Classical risk factors and smoking habit were evaluated in 354 men who completed health examinations annually without any current medications. Carotid intima-media thickness (IMT) was followed for 27.1±4.5 months. At baseline, both maximum and mean IMT significantly changed during 2-year follow-up. They tended to increase along with progression of smoking habit, with significantly greater maximum IMT in current smokers compared with never smokers. Both maximum and mean IMT significantly changed during 2-year follow-up, and tended to increase with progression of smoking habit, with maximum IMT being greatest for current smokers. Past smokers tended to have greater IMT increase than never smokers. Among smoking habit and some atherosclerotic risk markers that showed significant correlation with maximum IMT increase, stepwise regression showed that smoking habit and serum low-density lipoprotein-cholesterol (LDL-C) level were the only independent predictors. CONCLUSIONS: Significant 2-year progression of subclinical atherosclerosis was associated with continuous smoking and LDL-C. This was only partly moderated in past smokers despite complete reversal of inflammatory activation, suggesting another crucial factor for inhibiting accelerated progression of subclinical atherosclerosis in men.

H(2) mediates cardioprotection via involvements of K(ATP) channels and permeability transition pores of mitochondria in dogs.

PURPOSE: Inhalation of hydrogen (H(2)) gas has been shown to limit infarct size following ischemia-reperfusion injury in rat hearts. However, H(2) gas-induced cardioprotection has not been tested in large animals and the precise cellular mechanism of protection has not been elucidated. We investigated whether opening of mitochondrial ATP-sensitive K+ channels (mK(ATP)) and subsequent inhibition of mitochondrial permeability transition pores (mPTP) mediates the infarct size-limiting effect of H(2) gas in canine hearts. METHODS: The left anterior descending coronary artery of beagle dogs was occluded for 90 min followed by reperfusion for 6 h. Either 1.3% H(2) or control gas was inhaled from 10 min prior to start of reperfusion until 1 h of reperfusion, in the presence or absence of either 5-hydroxydecanoate (5-HD; a selective mK(ATP) blocker), or atractyloside (Atr; a mPTP opener). RESULTS: Systemic hemodynamic parameters did not differ among the groups. Nevertheless, H(2) gas inhalation reduced infarct size normalized by risk area (20.6±2.8% vs. control gas 44.0±2.0%; p<0.001), and administration of either 5-HD or Atr abolished the infarct size-limiting effect of H(2) gas (42.0±2.2% with 5-HD and 45.1±2.7% with Atr; both p<0.001 vs. H(2) group). Neither Atr nor 5-HD affected infarct size per se. Among all groups, NAD content and the number of apoptotic and 8-OHdG positive cells was not significantly different, indicating that the cardioprotection afforded by H(2) was not due to anti-oxidative actions or effects on the NADH dehydrogenase pathway. CONCLUSIONS: Inhalation of H(2) gas reduces infarct size in canine hearts via opening of mitochondrial K(ATP) channels followed by inhibition of mPTP. H(2) gas may provide an effective adjunct strategy in patients with acute myocardial infarction receiving reperfusion therapy.

The association between research funding status and clinical research papers' citation impact in Japan: A cross-sectional bibliometric study.

Introduction: Studies have not sufficiently clarified the differences in citation impact between funded and non-funded clinical research papers. Hence, this study seeks to evaluate the relation between research funding status and clinical research papers' citation impact in different research fields using multiple evaluation indices. Methods: In this cross-sectional bibliometric study, clinical research papers published by core clinical research hospitals in Japan were compared retrospectively in terms of times cited (TC), category normalized citation impact (CNCI), citation percentile (CP), journal impact factor (JIF), the Software to Identify, Manage, and Analyze Scientific Publications (SIGAPS) category, and whether they were the funded clinical research. The association between research funding status or the SIGAPS category and CNCI ≥ 2 was analyzed using logistic regression analysis. Results: 11 core clinical research hospitals published 553 clinical research papers, of which 120 were non-funded and 433 were funded (public institution-funded and industry-funded). The study found that funded clinical research papers (public institution-funded and industry-funded) had significantly higher TC, CNCI, CP, and JIF than non-funded ones [TC: 8 (3-17) vs. 14 (8-31), p < 0.001; CNCI: 0.53 (0.19-0.97) vs. 0.87 (0.45-1.85), p < 0.001; CP: 51.9 (24.48-70.42) vs. 66.7 (40.53-88.01), p < 0.001; JIF: 2.59 (1.90-3.84) vs. 2.93 (2.09-4.20) p = 0.008], while the proportion of A or B rank clinical research papers of the SIGAPS category was not significantly different between the two groups (30.0 vs. 34.9%, p = 0.318). In the logistic regression analysis, having a CNCI ≥ 2 was significantly associated with research funding (public institution-funded and industry-funded) and publication in A or B rank journals of the SIGAPS category [research funding: Estimate 2.169, 95% confidence interval (CI) 1.153-4.083, p = 0.016; SIGAPS category A/B: Estimate 6.126, 95% CI 3.889-9.651, p < 0.001]. Conclusion: Analysis via multiple indicators including CNCI and the SIGAPS category, which allows for a comparison of the papers' citation impact in different research fields, found a positive relation between research funding status and the citation impact of clinical research papers.

Isoform-specific intermolecular disulfide bond formation of heterochromatin protein 1 (HP1).

Three mammalian isoforms of heterochromatin protein 1 (HP1), α, ß, and γ, play diverse roles in gene regulation. Despite their structural similarity, the diverse functions of these isoforms imply that they are additionally regulated by post-translational modifications. Here, we have identified intermolecular disulfide bond formation of HP1 cysteines in an isoform-specific manner. Cysteine 133 in HP1α and cysteine 177 in HP1γ were involved in intermolecular homodimerization. Although both HP1α and HP1γ contain reactive cysteine residues, only HP1γ readily and reversibly formed disulfide homodimers under oxidative conditions. Oxidatively dimerized HP1γ strongly and transiently interacted with TIF1ß, a universal transcriptional co-repressor. Under oxidative conditions, HP1γ dimerized and held TIF1ß in a chromatin component and inhibited its repression ability. Our results highlight a novel, isoform-specific role for HP1 as a sensor of the cellular redox state.

Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload.

BACKGROUND: Apoptosis may contribute to the development of heart failure, but the role of apoptotic signaling initiated by the endoplasmic reticulum in this condition has not been well clarified. METHODS AND RESULTS: In myocardial samples from patients with heart failure, quantitative real-time polymerase chain reaction revealed an increase in messenger RNA for C/EBP homologous protein (CHOP), a transcriptional factor that mediates endoplasmic reticulum-initiated apoptotic cell death. We performed transverse aortic constriction or sham operation on wild-type (WT) and CHOP-deficient mice. The CHOP-deficient mice showed less cardiac hypertrophy, fibrosis, and cardiac dysfunction compared with WT mice at 4 weeks after transverse aortic constriction, although the contractility of isolated cardiomyocytes from CHOP-deficient mice was not significantly different from that in the WT mice. In the hearts of CHOP-deficient mice, phosphorylation of eukaryotic translation initiation factor 2alpha, which may reduce protein translation, was enhanced compared with WT mice. In the hearts of WT mice, CHOP-increased apoptotic cell death with activation of caspase-3 was observed at 4 weeks after transverse aortic constriction. In contrast, CHOP-deficient mice had less apoptotic cell death and lower caspase-3 activation at 4 weeks after transverse aortic constriction. Furthermore, the Bcl2/Bax ratio was decreased in WT mice, whereas this change was significantly blunted in CHOP-deficient mice. Real-time polymerase chain reaction microarray analysis revealed that CHOP could regulate several Bcl2 family members in failing hearts. CONCLUSIONS: We propose the novel concept that CHOP, which may modify protein translation and mediate endoplasmic reticulum-initiated apoptotic cell death, contributes to development of cardiac hypertrophy and failure induced by pressure overload.

Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures.

Heart diseases due to myocardial ischemia, such as myocardial infarction or ischemic heart failure, are major causes of death in developed countries, and their number is unfortunately still growing. Preliminary exploration into the pathophysiology of ischemia-reperfusion injury, together with the accumulation of clinical evidence, led to the discovery of ischemic preconditioning, which has been the main hypothesis for over three decades for how ischemia-reperfusion injury can be attenuated. The subcellular pathophysiological mechanism of ischemia-reperfusion injury and preconditioning-induced cardioprotection is not well understood, but extensive research into components, including autacoids, ion channels, receptors, subcellular signaling cascades, and mitochondrial modulators, as well as strategies for modulating these components, has made evolutional progress. Owing to the accumulation of both basic and clinical evidence, the idea of ischemic postconditioning with a cardioprotective potential has been discovered and established, making it possible to apply this knowledge in the clinical setting after ischemia-reperfusion insult. Another a great outcome has been the launch of translational studies that apply basic findings for manipulating ischemia-reperfusion injury into practical clinical treatments against ischemic heart diseases. In this review, we discuss the current findings regarding the fundamental pathophysiological mechanisms of ischemia-reperfusion injury, the associated protective mechanisms of ischemic pre- and postconditioning, and the potential seeds for molecular, pharmacological, or mechanical treatments against ischemia-reperfusion injury, as well as subsequent adverse outcomes by modulation of subcellular signaling mechanisms (especially mitochondrial function). We also review emerging translational clinical trials and the subsistent clinical comorbidities that need to be overcome to make these trials applicable in clinical medicine.